Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated rat pancreatic beta cells in monolayer culture were shown to be protected from the cytotoxic effect of streptozotocin (STZ) by allopurinol. Pretreatment with allopurinol for 2 h caused dose-dependent inhibition of the decreased secretion of insulin by the cells induced by STZ (2 mM, for 1 h), 500 microM allopurinol causing complete inhibition of this effect of STZ. Pretreatment with allopurinol (250 microM) also prevented the rapid decrease in intracellular adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide concentrations in beta cells induced by treatment with STZ. High performance liquid chromatography revealed that the intracellular concentration of uric acid in STZ-treated cells was about 3 fold that of control cells. This finding suggests that the reaction of xanthine oxidase is facilitated in the cells exposed to STZ probably due to an increased supply of substrate resulting from decrease in intracellular ATP. Based on these results, a possible mechanism of the effect of allopurinol on the cytotoxic effect of STZ via xanthine oxidase is discussed.
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PMID:Allopurinol protects pancreatic beta cells from the cytotoxic effect of streptozotocin: in vitro study. 214 33

To investigate a possible role of free radical production by xanthine oxidase in the pathogenesis of ethanol-induced hepatic lipid peroxidation, chow-fed rats were given ethanol (5 g/kg) and placed at 32 degrees C for 6 h, which resulted in increased hepatic malondialdehyde levels. Pretreatment with allopurinol in amounts that effectively inhibited xanthine metabolism also significantly decreased ethanol-induced lipid peroxidation, suggesting participation of free radicals produced by xanthine oxidase in the peroxidative process. Both acetaldehyde and purine can serve as substrates for xanthine oxidase. Pretreatment with cyanamide increased hepatic acetaldehyde levels 5-fold, yet this was associated with a decrease in lipid peroxidation, indicating that acetaldehyde is not the xanthine oxidase substrate involved. By contrast, ethanol increased hepatic contents of hypoxanthine and xanthine and enhanced urinary output of allantoin (a final product of xanthine metabolism), incriminating increased metabolism of purines. Ethanol administration also enhanced hepatic nicotinamide adenine dinucleotide (reduced form). A corresponding rise of nicotinamide adenine dinucleotide (reduced form) in vitro inhibited xanthine dehydrogenase activity by 60%-76%. Increased purine degradation, possibly associated with a shift from the dehydrogenase to the xanthine oxidase pathway (secondary to nicotinamide adenine dinucleotide [reduced form]-mediated inhibition of xanthine dehydrogenase activity) is proposed as a possible mechanism for ethanol-stimulated free radical production. Because allopurinol attenuates the associated lipid peroxidation, this agent might be considered for possible therapeutic use in alcohol-induced liver damage.
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PMID:Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats. 229 79

To investigate mechanisms of ATP depletion in human umbilical vein endothelial cells after oxidant injury, we studied the relationship between DNA damage, activation of the DNA-repairing enzyme poly ADP-ribose polymerase, NAD depletion, and ATP depletion. We found that oxidant stress generated with hypoxanthine-xanthine oxidase and glucose-glucose oxidase resulted in profound DNA damage. When endothelial cells were exposed to 25 and 50 mU/ml xanthine oxidase for 60 min, the percentage of double-stranded DNA was significantly reduced (p less than 0.05) to 15.2 +/- 1.2 and 4.6 +/- 0.5%, respectively, compared to 75.7 +/- 3.9% for control cells. When endothelial cells were exposed to 25 and 50 mU/ml glucose oxidase for 60 min, the percentage of double-stranded DNA was significantly (p less than 0.05) reduced to 35.0 +/- 1.5% and 9.9 +/- 7.7%, respectively, compared to 73.2 +/- 2.4% for control cells. ATP and NAD levels declined simultaneously with DNA damage. Because activation of the DNA-repairing enzyme poly ADP-ribose polymerase can consume NAD sufficient to interfere with ATP synthesis, we studied NAD and ATP levels after oxidant injury when ADP-ribose polymerase was inhibited with 3-aminobenzamide and nicotinamide. When poly ADP-ribose polymerase was inhibited, NAD levels remained normal, but ATP depletion was not prevented. We conclude that oxidant injury to human umbilical vein endothelial cells results in profound DNA damage and NAD and ATP depletion. NAD depletion results from activation of poly ADP-ribose polymerase, but this phenomenon is not the mechanism of ATP depletion in human umbilical vein endothelial cells.
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PMID:Mechanisms of endothelial cell ATP depletion after oxidant injury. 252 33

Xanthine oxidase activity in the rat brain was measured by means of high-performance liquid chromatography with electrochemical detection of uric acid. Cerebral ischemia was produced by a four-vessel occlusion method. In the control rat, the enzyme activity was 0.87 +/- 0.13 nmol/gm wet weight/min at 25 degrees C (mean +/- standard deviation), of which 92.4% was associated with the nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase form and only 7.6% with the oxygen-dependent superoxide-producing oxidase form. However, the ratio of the latter form increased to 43.7% after 30 minutes of global ischemia, despite the total xanthine oxidase activity remaining the same. Thus, it was revealed that uric acid can be synthesized in the rat brain and that cerebral ischemia induced the conversion of xanthine oxidase from an NAD-dependent dehydrogenase to an oxygen-dependent superoxide-producing oxidase. Although the xanthine oxidase pathway has been proposed as a source of oxygen-derived free radicals in various ischemic organs other than brain, the results of the present study suggest the involvement of the oxygen free radicals generated from this pathway in the pathogenesis of the ischemic injury of the rat brain.
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PMID:Changes in xanthine oxidase in ischemic rat brain. 254 24

Mitomycin C (MC) is a naturally occurring anticancer agent which has been shown to be more cytotoxic to hypoxic tumor cells than to their aerobic counterparts. The mechanism of action of this agent is thought to involve biological reductive activation, to a species that alkylates DNA. A comparison of the cytotoxicity of MC to EMT6 tumor cells with that of the structural analogues porfiromycin (PM), N-(N',N'-dimethylaminomethylene)amine analogue of mitomycin C (BMY-25282), and N-(N',N'-dimethylaminomethylene)amine analogue of porfiromycin (BL-6783) has demonstrated that PM is considerably less cytotoxic to aerobic EMT6 cells than MC, whereas BMY-25282 and BL-6783 are significantly more toxic. The relative abilities of each of these compounds to generate oxygen free radicals following biological activation were measured. Tumor cell sonicates, reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, xanthine oxidase, and mitochondria were used as the biological reducing systems. All four mitomycin antibiotics produced oxygen radicals following biological reduction, a process that may account for the aerobic cytotoxicity of agents of this class. The generation of relative amounts of superoxide and hydroxyl radical were also measured in EMT6 cell sonicates. BMY-25282 and BL-6783 produced significantly greater quantities of oxygen free radicals with the EMT6 cell sonicate, reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, and mitochondria than did MC and PM. In contrast, BMY-25282 and BL-6783 did not generate detectable levels of free radicals in the presence of xanthine oxidase, whereas this enzyme was capable of generating free radicals with MC and PM as substrates. MC consistently produced greater amounts of free radicals than PM with all of the reducing systems. BMY-25282, BL-6783, and MC all generated hydroxyl radicals, while PM did not appear to form these radicals. The findings indicate that a correlation exists between the ability of the mitomycin antibiotics to generate oxygen radicals and their cytotoxicity to aerobic EMT6 tumor cells.
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PMID:Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. 301 Dec 50

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. Km values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 microM, and that of deflavo xanthine oxidase in the range of 39-over 200 microM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxy radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.
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PMID:Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen. 302

The relative amounts of monofunctional and bifunctional alkylation products of DNA with mitomycin C (MC) depend on whether one or both masked alkylating functions of MC are activated reductively; adduct 8 is the result of one function and adducts 7 and 9, formed as a pair, are the result of both functions being activated [Tomasz, M., Lipman, R., Chowdary, C., Pawlak, J., Verdine, G. L., & Nakanishi, K. (1987) Science (Washington, D.C.) 235, 1204-1208]. To determine the mechanism governing this differential reactivity of MC with DNA, MC-Micrococcus luteus DNA complexes formed under varying conditions in vitro were digested to nucleosides and adducts. Adduct distribution, analyzed by high-performance liquid chromatography, served as the measure of monofunctional and bifunctional activation. H2/PtO2 and xanthine oxidase/reduced nicotinamide adenine dinucleotide (NADH) activated MC mostly monofunctionally, and Na2S2O4 activated the drug bifunctionally under comparable conditions. Excess MC selectively suppressed, but excess PtO2 selectively promoted, bifunctional activation by H2/PtO2; excess xanthine oxidase and/or NADH also had promoting effects. O2 tested in the Na2S2O4 system was inhibitory. 10-Decarbamoyl-MC acted strictly monofunctionally under all conditions. Monoadducts bound to DNA were converted to bis adducts upon rereduction. A mechanism with the following features was derived: (i) Activation of MC at C-1 and C-10 is sequential (C-1 first). (ii) A one-time reduction is sufficient for both. (iii) Activation of the second function may be selectively inhibited by kinetic factors or O2. (iv) 7 and 9 are coproducts of bifunctional activation; their ratio depends on the DNA base sequence. (v) Activation of the second function involves an iminium intermediate. Direct applications to the action of MC in vivo are discussed.
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PMID:Mechanism of monofunctional and bifunctional alkylation of DNA by mitomycin C. 313 45

Rat liver cytosol and buttermilk xanthine oxidase both converted 7-deoxypyrromycinone, the 7-deoxyaglycone of marcellomycin, a new anthracycline antibiotic, to a nonfluorescent compound under anaerobic conditions and in the presence of an electron donor. Reduced nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate were equally effective electron donors for liver cytosol, and xanthine was the best cofactor for xanthine oxidase. However, xanthine was inactive with liver cytosol. Reactions with xanthine oxidase obeyed Menten-Michaelis kinetics and were inhibited by allopurinol. No xanthine oxidase activity was detected in liver cytosol. Xanthine oxidase also induced a loss of fluorescence when incubated with 7-deoxydaunorubicin aglycone. The nonfluorescent metabolite of 7-deoxypyrromycinone was tentatively identified as the dihydroquinonic derivative of the parent deoxyaglycone on the basis of its spectrophotometric, fluorescent, thin layer chromatographic, and mass spectral characteristics. Our data demonstrate that more than one enzymatic activity, xanthine oxidase, and an unidentified rat liver cytosolic enzyme convert the 7-deoxyaglycones of anthracycline antibiotics to nonfluorescent metabolites.
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PMID:Loss of fluorescence by anthracycline antibiotics: effects of xanthine oxidase and identification of the nonfluorescent metabolites. 346 41

The mechanism of the enhancing effect of methyl viologen (MV) and flavin-adenine dinucleotide (FAD) on sulfoxide reduction which is mediated by a combination of aldehyde oxidase (AO) from guinea pig liver and one-electron reducing flavoenzymes, such as milk xanthine oxidase (XO), was examined. The activity of anaerobic reduction of diphenyl sulfoxide (DPSO) to diphenyl sulfide (DPS) was less than 1 nmol/min/mg protein of AO preparation in a system consisting of hypoxanthine, XO and AO. However, the sulfoxide reduction by this system was enhanced about 6- and 100-fold by the additions of FAD and MV, respectively. In the system containing MV or FAD, other one-electron reducing flavoenzymes such as nicotinamide adenine dinucleotide (reduced form) (NADH) dehydrogenase, lipoamide dehydrogenase and glutathione reductase with an appropriate electron donor, could replace XO. The ability of supplemented flavoenzymes to facilitate DPSO reduction correlated with their abilities to reduce MV and FAD. When AO was omitted from the combined system, no sulfoxide reduction was observed. Stoichiometric study revealed that MV semiquinone and FADH2 were oxidized at ratios of 2 and 1 mol, respectively, per mol of DPS formed. These results indicate that either MV or FAD serves as an electron carrier from the supplemented flavoenzymes to AO, a terminal reductase of sulfoxide.
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PMID:Sulfoxide reduction catalyzed by guinea pig liver aldehyde oxidase in combination with one-electron reducing flavoenzymes. 383 63

The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
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PMID:Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency. 395 May 45


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